1. Field of the Invention
The invention is generally related to the art of pharmaceutical manufacturing and methods of production. Specifically, it is related to processes of sterilizing a pharmaceutical composition comprising a suspension of an insoluble component in an aqueous phase while maintaining the redispersibility, homogeneity, uniformity and particle particle size of the suspension.
2. Description of Related Art
The need for sterility in certain pharmaceutical formulations is mandated both by concerns for the general public's safety, and a pharmaceutical company's reputation for producing quality products. Formulations intended for the ears in general ("otic") and eyes in particular ("opthalmic") are mandated by the FDA to be sterile, even though after the first access to what is intended to be a multi-use package, they will lose their sterility for subsequent uses.
To produce a sterile pharmaceutical suspension product is technically a challenging task. Today it is common to use the following five techniques and/or chemicals for sterilizing any given pharmaceutical suspension product: wet steam (autoclaving), dry heat, aseptic filtration, ethylene oxide, and irradiation.
All of the present methods have deficiencies or limitations. The first two methods involve a high degree of heat, and only chemically thermostable materials or products can be sterilized by these methods. Additionally, in the case of a suspension product, heat also impacts unfavorably on the physical attributes of the suspension by altering flocculation, sedimentation, and redispersion characteristics of the suspended particles. In many cases heat affects the homogeneity or uniformity of the final product either by catalyzing the formation of loose agglomerations called "curds," or, if the curds become compacted and fuse, "cakes" of suspended particles. Curds and cakes negatively impact on the patient or caregiver's ability to re-suspend the product easily and provide uniform dosing.
The aseptic filtration technique cannot be utilized for suspension products due to non-filterability of suspended particles, which requires passing the product through a 0.22 .mu.m filter, and is suited only for solution products with low to moderate viscosity which can be filtered through such a fine filter.
The ethylene oxide method has been a widely used method for suspension products where product or components are thermolabile. Most of the currently marketed suspension products utilize this technique where individual components are sterilized by this method and then processed or assembled together aseptically. The technique, however, requires the elimination of residual ethylene oxide from the product which is a time consuming and difficult process with still some ethylene oxide left. Most of the products sterilized by this method were introduced in the market decades ago, and probably would not be allowed to be introduced today due to present day's stringent regulatory requirement for almost zero ethylene oxide residue.
Finally, the radiation technique causes immense analytical difficulties due to its possible degradative impact on the pharmaceutical components, and therefore is avoided in the industry. Only packaging components, or containers etc. are sterilized by this method. Safety for human exposure is also a concern.
Procedures for sterilizing suspensions include ethylene oxide exposure, and the wet steam method in combination with saturated sodium chloride, cited below in U.S. Pat. No. 3,962,430. As previously mentioned, the ethylene oxide method is being phased out, and so new methods are sought to sterilize suspensions. The main problem to be overcome in heating a suspension is the likelihood that the suspended material will dissolve in the aqueous solution at the high temperature necessary for sterilization, and then as the suspension cools it may recrystallize in different crystal form, shape and size than the original particles. This recrystallization and/or other thermal effects disrupts the overall homogeneity characteristics of the suspension, which are critical to good manufacturing practice and reliability of dispensing the suspension product. This is because suspensions which tend to settle out over time may form hard "cakes" which do not rediperse upon shaking.
U.S. Pat. No. 3,962,430 (O'Neil) is directed to a method of sterilization of insoluble non-electrolyte medicinal agents by heating in a aqueous suspension which contains saturated sodium chloride. Corticosteroids are given by example as the solid non-electrolyte medical agents, including as shown in Example 11, Hydrocortisone. The method shown depends upon the use of an over-saturated solution of NaCl, as discussed in column 2, lines 27-33. Solutions having less than saturated NaCl have significant drawbacks, including re-crystallization, as discussed in column 3, lines 51-61. The re-suspendability characteristics of the suspensions are not discussed.
Other patents disclose in a more general fashion aqueous suspensions of sparingly soluble pharmaceuticals, including U.S. Pat. No. 5,599,824 (Grunenberg et al.), U.S. Pat. No. 4,150,150 (Straub) and U.S. Pat. No. 4,892,741 (Ohm et al.).
There exists a need for more flexible methods of sterilizing suspensions having one or more water insoluble components.